Pharmacokinetic characterisation of Chronocort® - A new modified release oral formulation of hydrocortisone that mimics the endogenous circadian profile of cortisol

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 26-40-Glucocorticoid Actions & Disease
Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-26
Richard J. Ross*1, Martin Whitaker2, Miguel Debono2, Hiep Huatan3, Deborah P. Merke4 and Wiebke Arlt5
1Univ of Sheffield, Sheffield, United Kingdom, 2University of Sheffield, 3Diurnal Ltd, 4NIH, Bethesda, MD, 5University of Birmingham, Birmingham, United Kingdom
It is not possible with current immediate release oral formulations of hydrocortisone to fully replicate the circadian profile of endogenous cortisol. Physiological hormone replacement is important for patients with congenital adrenal hyperplasia as it addresses the critical overnight build-up of androgens and for patients with adrenal insufficiency as it may circumvent early morning fatigue.  Previous attempts to develop a circadian product of hydrocortisone, using a modified release tablet formulation, have suffered from the drawback of reduced bioavailability (Debono et al, JCEM 2009,94,1548-54). This was hypothesized to be due to the reduced lumenal exposure of hydrocortisone in the lower gut which is required to confer an extended drug delivery profile. We now report the development of a new, modified release, multiparticulate formulation of Chronocort®, which replicates the circadian profile of cortisol without compromising bioavailability. Pharmacokinetic evaluation of Chronocort® in healthy male adult volunteers, in whom cortisol secretion was supressed with dexamethasone, showed excellent comparability to the circadian profile of cortisol over the dose range of 20mg to 30mg. Following dosing of 30mg Chronocort®( 20mg at 23:00h and 10mg at 07:00h), the mean Tmax was achieved at 8h post-dosing with a corresponding mean Cmax of 665nmol/L (24 ug/dl). It was further observed that the splitting of the 30mg dose into a toothbrush regimen (last thing at night and first thing in the morning), the mean cortisol serum levels for the afternoon were consistently maintained above 200nmol/L (7ug/dl), in line with the endogenous cortisol profile observed in healthy controls. Over the evaluated dose range of 5mg to 30mg, Chronocort® exhibited dose linearity with a relative bioavailability (estimated from the AUC0-t  ratio of Chronocort® to hydrocortisone immediate release) of greater than 100%. We conclude from this study that Chronocort® has the potential to replicate the physiological circadian profile of cortisol without compromising the bioavailability of hydrocortisone.

Disclosure: RJR: Founder, Diurnal. MW: Board Member, Diurnal. HH: Board Member, Diurnal. DPM: Clinical Researcher, Diurnal. WA: Consultant, Diurnal. Nothing to Disclose: MD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This research was supported in part by the Intramural Research Program at the National Institutes of Health (NIH), Bethesda, US.
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